Heretofore, the copper complex of 6-methoxy-1-phenazinol 5,10-dioxide was prepared by combining a saturated solution of 6-methoxy-1-phenazinol 5,10-dioxide (myxin) in a suitable organic solvent with a saturated solution of a copper II salt in the same solvent. Organic solvents which have been employed include acetic acid, acetonitrile, methanol, ether, chloroform etc. The precursor, 6-methoxy-1-phenazinol 5,10-dioxide, is readily prepared by selective methylation of iodinin (1,6-phenazinol 5,10-dioxide) as, for example, by treating the monosodium salt of iodinin with a methylene agent such as dimethyl sulfate in an inert organic solvent. A solution of the 6-methoxy-1-phenazinol 5,10-dioxide when combined with a solution of a cupric salt, e.g., cupric acetate, forms a copper complex containing one mole of copper for every two moles of 6-methoxy-1-phenazinol 5,10-dioxide. Other suitable cupric salts included those of weak acids having pKa's of about 4.2 or higher, such as propionic or benzoic acids and those of mineral acids, such as cupric sulfate, which must be used in buffered solvent systems to avoid highly acidic conditions.
Since the final product is isolated from the reaction medium by precipitation, it is necessary to utilize a solvent or solvent mixture in which both the 6-methoxy-1-phenzinol 5,10-dioxide and the cupric salt are more soluble than the complex formed by their reaction.
This reaction is carried out at room temperature or at temperatures above room temperature to facilitate solution of the reactants and reduce the rather large amount of solvent needed.
The copper complex prepared by the organic solvent method has 90% of its particles below 10 microns in size and usually below 5 microns with the remaining 10% below 20 microns in size. On standing, however, the particles having a strong tendency to form aggregates of from about 400 to 600 microns in size. In order to provide an increased surface area and to afford sufficient solubility so as to achieve an effective degree of physiological activity in the various pharmaceutical preparation, the copper complex of 6-methoxy-1-phenazinol 5,10-dioxide must have this initial particle size distribution of 5-20 microns. However, since the material is thermal, shock and static-sensitive, the conventional means of deaggregation, e.g., jet milling or attrition, are too hazardous.
The aforesaid method of preparation of the copper complex of 6-methoxy-1-phenazinol 5,10-dioxide (hereinafter referred to as copper myxin) has, as noted above, several serious drawbacks. In the first place, because of the low solubility of myxin in organic solvents, a high solvent volume is required for its complexation. The preferred solvent, acetonitrile, is flammable and its use in conjunction with copper myxin is hazardous. In addition, myxin itself is highly flammable and sensitive to electrostatic discharge. Secondly, the initial copper myxin product is a very fine suspension making both filtration and washings difficult and tedious. Further, copper myxin particles, as noted above, have a very strong tendency to form, on standing, aggregates of from 400 to 600 microns in size, thus reducing their chemotherapeutic suitability. Since the material is ten times as sensitive to impact explosion as TNT, milling or grinding operations are very hazardous procedures.
It is an object of this invention, therefore, to provide a method for the preparation of copper myxin which will overcome the deficiencies and hazards of the previous procedure.